The present invention concerns a composite prosthesis for preventing postsurgical adhesions, and in particular finds application in the field of visceral or parietal surgery. The invention will be described by way of example in relation to a composite prosthesis intended for use in parietal surgery, in the repair of eventrations or hernias.
Postsurgical adhesions include all non-anatomical fibrous connections accidentally induced by a surgical act during the normal process of cicatrization. They may occur in all surgical disciplines regardless of the operation in question. They are generally all the more severe, the greater the surgical trauma and the more affected the tissues which normally ensure the planes of division (interstitial connective tissue, the synovial membranes, the tendon sheaths, peritoneal and pleural serosa, etc.). Any surgical trauma to tissue is followed by a cascade of physiological events, the main times of which can be simplified as follows:
time zero (t0): surgical trauma, capillary invasion;
time zero plus a few minutes: coagulation, formation of fibrin network, release of chemotactic factors;
time zero (t0) plus 12 to 48 hours: influx of leukocytes, predominantly polynuclears;
time zero (t0) plus 24 hours to 5 days: influx of leukocytes, predominantly macrophages;
time zero (t0) plus 4 to 8 days: influx of fibroblasts;
time zero (t0) plus 5 to 14 days: conjunctive differentiation of the cicatricial reaction;
time zero (t0) plus 15 to 180 days: cicatricial remodeling.
Although some of the exact mechanisms are still unknown, particularly as regards determination of the intensity of the reaction, it appears that the first few days are decisive since they condition the influx of fibroblasts responsible for the formation of adhesions.
For this reason, such postsurgical adhesions can provoke syndromes which can be classed principally as chronic pain, occlusive syndromes and female infertility. Furthermore, they increase very substantially the risks of making errors in follow-up surgery (myocardial or intestinal invasion during repeat thoracotomy or laparotomy), while prolonging the operating times, since the preliminary dissection can be very awkward in such cases.
One solution to this problem consists in interposing a physical barrier between the structures which one does not wish to see adhering. However, the desired barrier effect poses the problem of the intrinsic adhesive power of this barrier. The reason is that if the barrier is made of a nonabsorbable material, it can itself be the source of adhesions over the course of time; and if it is absorbable, its absorption must be sufficiently noninflammatory so as not to cause adhesions itself.
Several properties are therefore necessary if a material is to be able to reduce the risk of adhesions, namely, among others:
the material of which it is made up or composed must be substantially smooth and nonporous on at least one of its surfaces, so as not to offer space for cell recolonization;
the surface of the material must limit the original cell adhesion.
In order to remedy this problem, hydrophobic and inert artificial polymers have been used, for example expanded PTFE, or absorbable polymer substances, for example those based on hyaluronates, or on modified cellulose, which substances rapidly form a hydrogel by hydration in the body.
Nevertheless, and in particular in visceral and parictal surgery, but also in orthopedic or neurological surgery, the barrier must also have a certain mechanical strength allowing it to fulfill its function as an element of surgical reconstruction. Generally speaking, the known prosthetic fabrics, particularly in the treatment of parietal insufficiencies, for example hernias and eventrations, afford an additional mechanical strength to the surgical reconstruction. Such fabrics are all the more effective and their local tolerance is all the better, the earlier and the more intimate their tissue integration. For this reason, the most effective of the known prosthetic fabrics for these indications are generally highly porous and are designed in such a way as to be integrated in the body as rapidly as possible. The term xe2x80x9cporousxe2x80x9d is intended to signify the characteristic according to which at least one of the surfaces of the fabric is rough, so as to present alveoli, distributed regularly or irregularly, and promoting all cell colonization. It is for this reason that upon contact with the viscera for example, these fabrics promote adhesion, which limits their use at the so-called preperitoneal or retroperitoneal sites. Now, in a number of cases, and more particularly in the case of multiple recurring eventrations, implantation strictly in the preperitoneal site is difficult, even impossible, on account of the existence of an extensive deficit of serosa.
There is therefore a requirement to make available a product which is able to solve the problem of preventing postsurgical adhesions, while at the same time offering a prosthetic reinforcement subject to cell recolonization and tissue integration, and which can be used, for example, to treat an eventration involving substantial peritoneal loss, or small eventrations, by laparoscopy, and hernias.
To this end, patent application WO-A-96/08277 describes a composite prosthesis comprising a prosthetic fabric, in this case an absorbable or nonabsorbable lattice, and at least one film of a crosslinked collagenous material, in this case a collagen gel coagulated in the dry state, associated with one surface of the prosthetic fabric. The composite prosthesis thus formed finds an application in the treatment of eventrations and hernias and, according to the inventors, prevents postoperative adhesions because the coliagenous membrane constitutes a zone of separation permitting release of any early postoperative adhesions that may develop. It is apparent from experiments carried out on pigs and described in the application that the absorption time of the collagenous membrane remains long.
Since any absorption of material is relatively proinflammatory, the persistence beyond about ten days of an absorbable material can lead to a delay in the disappearance of inflammatory cells at the site. This persistent presence of active inflammatory cells (essentially macrophages) will trigger an activation cascade resulting in the stimulation of fibroblasts, which themselves are responsible for the direct formation of adhesions. While mesothelial cells, which are responsible for the peritoneal covering, are known for their rapid regeneratability (appearance as of the fifth or sixth day), it is therefore not only unnecessary, but also substantially contrary to the principles of adhesion prevention, to keep the material on which the barrier effect relies beyond eight to ten days after surgery.
Thus, the use of the collagenous membrane combined with the synthetic lattice, as described in the aforementioned patent application, may in some cases be responsible for initial adhesions because of its relatively slow absorption and may therefore be unsuitable for solving the problem of preventing postsurgical adhesions, while at the same time offering a prosthetic reinforcement subject to cell recolonization and tissue integration. Moreover, its relatively slow absorption limits effective and early recolonization of the synthetic lattice, the latter being masked by the collagenous membrane at the moment when it has to be integrated, that is to say during the first two weeks.
Consequently, the subject of the invention is a composite prosthesis of the kind defined in document WO-A-96/08277, allowing effective tissue integration while remaining compatible with rapid absorption of the film of collagenous material.
According to the invention, this compromise is achieved by the cooperation of three characteristics, namely:
a) the choice of a particular lattice, in this case a three-dimensional prosthetic fabric, that is to say a fabric having a certain thickness separating its two surfaces; and one surface of the fabric is open to any postsurgical cell colonization;
b) linkage, at least on the surface, or even to a certain depth, of the collagenous film to the other surface of said fabric, and that is to say that surface on the opposite side from the surface open to cell colonization;
c) and the choice of a particular collagenous material, namely a collagen whose helical structure is, at least partially, thermally denatured without hydrolytic degradation.
This cooperation makes it possible for tissue colonization to develop immediately, completely independently of absorption of the collagenous film, which itself is relatively rapid, for example occurring in about ten days, on account of the retained collagenous material, and without compromising in any way the monolithic character of the composite prosthesis.
By virtue of the invention, the tissue integration time and the collagenous-material absorption time become of the same order of magnitude, which means that in most cases, when the fabric has been completely integrated and is mechanically effective, for example on the internal surface of the abdominal wall, the collagenous material is completely absorbed, thereby excluding any subsequent adherability of the composite prosthesis.
By virtue of the invention, the parietal or visceral integration of the prosthesis is not disturbed by the absorption of the collagenous material.
The term xe2x80x9copen surfacexe2x80x9d is intended to signify that said surface includes alveoli having a certain depth according to the thickness of the three-dimensional fabric, these alveoli passing completely or incompletely through the thickness of the fabric, from one surface to the other. In the case of a complete passage of the alveoli, this will be referred to as an openwork prosthetic fabric.
According to the invention, that surface of the collagenous film opposite the prosthetic fabric is preferably substantially smooth and nonporous.
The prosthetic fabric comprises, for example, two opposed porous surfaces, separated from each other by the thickness of said fabric, but connected to each other by linking yarns.
By way of example, the weave of the prosthetic fabric determines, within the thickness of the latter, a multiplicity of transverse channels or alveoli, which are substantially parallel to one another, opening out on either side of said fabric on the two porous surfaces respectively, and of which the internal section is substantially free of any linking yarn.
Preferably, the collagenous material comprises collagen and at least one macromolecular hydrophilic additive chemically unreactive with respect to collagen.
The expression xe2x80x9cchemically unreactive with respect to collagenxe2x80x9d should be understood to mean a compound which is incapable of reacting with any collagen present and which in particular does not form covalent bonds with the latter during its crosslinking.
Advantageously, the thickness of the film is less than the thickness of the prosthetic fabric, for example between 2% and 10% of the total thickness of the composite prosthesis, and preferably between approximately 30 xcexcand 100 xcexcm, and more preferably still is approximately 50 xcexcto 75 xcexc.
Preferably, the collagenous material comprises collagen modified by oxidative scission and heating above 37xc2x0 C., crosslinked in the presence of at least one macromolecular hydrophilic additive chemically unreactive with respect to said collagen.
In general, this collagenous material may be obtained by the following process, which comprises the steps consisting in:
preparing a solution of collagen modified by oxidative scission;
treating said solution by heating to a temperature greater than 37xc2x0 C.;
mixing the resulting collagenous solution with a solution containing at least one macromolecular hydrophilic additive chemically unreactive with respect to collagen;
adjusting the pH of said mixture to a neutral pH.
The collagenous material which results therefrom and which forms part of the composite prosthesis of the invention is biocompatible and nontoxic and is absorbed in vivo in less than two weeks. It does not matter whether the collagen used to form the collagenous solution is of animal or human origin, but it is preferably native collagen, dissolved at acid pH or after treatment by pepsin digestion. In particular, it may be type I bovine collagen or type I or III human collagen, or else mixtures of the latter in any proportions.
The oxidative scission step preferably takes place with the aid of periodic acid or one of its salts, in order to make it self-crosslinkable, and thus the crosslinking can be carried out without the aid of crosslinking agents.
The film is linked at least on the surface to the prosthetic fabric, and preferably over a certain thickness, by capillary absorption of the constituent fibers in the prosthetic fabric.
Even more preferably, the collagenous material is in the form of a film linked by capillary absorption of the constituent fibers of the prosthetic fabric over a depth of less than 750 xcexcm, measured from the outer surface of the film.
Advantageously, the macromolecular hydrophilic additive has a molecular weight of greater than 3000 daltons and is preferably a hydrophilic polymer having a molecular weight of between 3000 and 20,000 daltons. Such additives are, for example, polyethylene glycol, polysaccharides, such as starch, dextran and cellulose, and modified polysaccharides carrying carboxylic functional groups. Preferably, the macromolecular hydrophilic additive is polyethylene glycol.
The weight concentration of hydrophilic additive is preferably two to ten times less than that of the collagen. The crosslinking of the collagen may be carried out at a temperature of between 4xc2x0 C. and 30xc2x0 C., and preferably between 18xc2x0 C. and 25xc2x0 C.
Advantageously, the composite prosthesis includes a film consisting of a collagen, as defined above, and of at least one macromolecular hydrophilic additive in a collagen/hydrophilic additive weight ratio from 1/1 to 9/1, preferably from 2/1 to 4/1 and more preferably 3/1.
According to the invention, a composite prosthesis comprises two surfaces which are different in their respective appearances and functions, namely one surface which is porous or open on one side, in order to accommodate and direct the postsurgical cell colonization, and the other surface which is closed, for tissue separation without adhesion.
The film of collagenous material is preferably continuous, smooth and nonporous, entirely covering the prosthetic fabric, and more preferably projects beyond the edges of the latter in such a way as to protect the prosthesis from visceral contacts, the overshoot being from 5 to 10 millimeters for example.
The film is intimately linked to the fabric by surface penetration, and cannot be delaminated, so as not to constitute a plane of separation, while at the same time maintaining the porosity open on the other surface of the prosthetic fabric.
The film is preferably also flexible so as to preserve the handleability of the product, and its possible use by the celioscopic route.
Once rehydrated, the film restores to the prosthetic fabric its initial mechanical properties (flexibility and elasticity) without fragmenting, and without making the fixation of the prosthesis more difficult. It is additionally transparent, and cannot stick when being put into position. Its rapid absorption ensures protection against the initial adhesive phenomena, that is to say in the first week following surgery, or in other words during the period of time necessary for the integration of the opposite surface. Upon its absorption, its weakly inflammatory and/or immunogenic character does not disturb the tissue colonization on the opposite side of said film.